胃肠胰神经内分泌肿瘤（GEP-NET）是罕见且高度异质性的新生物，其发病率在过去几十年中显著增加。基于肿瘤细胞增殖指数的分级系统预测G3 NET的高风险。然而，低中度分级（G1/G2）NET的临床进展不可预测，因为其变化从慢性到高度恶性都有可能。人类癌细胞的培养使得进行功能干预分析成为可能，这对于增进我们对癌症生物学的理解至关重要。到目前为止，尚未报道过针对G1/G2 NET的可持续、可靠的长期培养方法，以便进行疾病建模和药物筛查。在此，我们报告了首例长期培养的G2转移性小肠NET，它保留了肿瘤的主要遗传驱动因素并保持了内分泌细胞系的表达模式。这种长期培养模型显示出低增殖指数，并且可以连续传递而不会出现剧烈的核型变化。该模型可随时用于使用靶向剂进行药物筛查，并且在体内展现出低肿瘤形成能力。总的来说，这是第一个长期培养NET的模型，它在许多方面忠实地重现了原发性神经内分泌瘤的特征。版权所有©2023 D’Agosto、Fiorini、Pezzini、Delfino、Simbolo、Vicentini、Andreani、Capelli、Rusev、Lawlor、Bassi、Landoni、Pea、Luchini、Scarpa和Corbo。

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and highly heterogeneous neoplasms whose incidence has markedly increased over the last decades. A grading system based on the tumor cells' proliferation index predicts high-risk for G3 NETs. However, low-to-intermediate grade (G1/G2) NETs have an unpredictable clinical course that varies from indolent to highly malignant. Cultures of human cancer cells enable to perform functional perturbation analyses that are instrumental to enhance our understanding of cancer biology. To date, no tractable and reliable long-term culture of G1/G2 NET has been reported to permit disease modeling and pharmacological screens. Here, we report of the first long-term culture of a G2 metastatic small intestinal NET that preserves the main genetic drivers of the tumor and retains expression patterns of the endocrine cell lineage. Replicating the tissue, this long-term culture showed a low proliferation index, and yet it could be propagated continuously without dramatic changes in the karyotype. The model was readily available for pharmacological screens using targeted agents and as expected, showed low tumorigenic capacity in vivo. Overall, this is the first long-term culture of NETs to faithfully recapitulate many aspects of the original neuroendocrine tumor.Copyright © 2023 D’Agosto, Fiorini, Pezzini, Delfino, Simbolo, Vicentini, Andreani, Capelli, Rusev, Lawlor, Bassi, Landoni, Pea, Luchini, Scarpa and Corbo.